Hormones such as the indole hormone, melatonin, are widely found in both the plant and animal kingdoms. Melatonin can be found in human milk, bananas, beets, cucumbers, and tomatoes. Chemically, melatonin is N-acetyl-5-methoxytrypta mine, a derivative of serotonin, which in turn is derived from tryptophan. Melatonin is a ubiquitous natural neurotransmitter-like compound produced primarily by the pineal gland and is involved in numerous aspects of the biological and physiologic regulation of body functions. See, e.g., Malhotra, S., et al., Medscape General Medicine 2004; 6(2), 46; and www.nlm.nih.gov/medlineplus/print/druginfo/natural/patient-melatonin.html for a further background discussion.
The role of endogenous melatonin in circadian rhythm disturbances and sleep disorders is well established. Some studies have shown that melatonin may also be effective in breast cancer, fibrocystic breast diseases, and colon cancer. Melatonin has been shown to modify immunity, the stress response, and certain aspects of the aging process; some studies have demonstrated improvements in sleep disturbances and in instances of jet lag disturbances. The antioxidant role of melatonin may be of potential use for conditions in which oxidative stress is involved in the pathophysiologic processes. The multiplicity of actions and variety of biological effects of melatonin suggest the potential for a range of clinical and wellness-enhancing uses, especially considering that as one ages, the production of this key hormone goes into steady decline. Indeed, for an octogenarian, the amount produced is quite nominal.
Through melatonin release, the pineal gland maintains the internal clock governing the natural rhythms of body function. This apparent clock-setting property of melatonin has led to the suggestion that it is a “chronobiotic” substance that alters and potentially normalizes biological rhythms and adjusts the timing of other critical processes and biomolecules (hormones, neurotransmitters, etc.) that, in turn, exert numerous peripheral actions. The sleep-inducing effects of melatonin have advantages over conventional hypnotics, since melatonin, itself, is not a hypnotic drug. Melatonin only induces a natural state of sleepiness, and does not have the adverse side-effects of conventional hypnotics and prescription sleeping aids.
Melatonin has previously been used pharmaceutically, and has been prepared for oral administration (see, e.g., WO 1995/003043). These preparations include melatonin formulated with a cyclodextrin (WO 1999/047175), and as a microemulsion (U.S. Pat. No. 5,362,745). However, as with most oral preparations, it can take more than 30 minutes, even upwards of over an hour, after administration for the blood plasma concentration of melatonin to reach its peak. Goldberg, M J, Bergstrom, R F R, Smith, B P, Simcox, E A, Thomasson, H R, Shipley, L A: Sleep Research 1997: 26:101. This is due, in part, to the need for gastrointestinal absorption to occur before the melatonin is available in the bloodstream.
Further, melatonin has low oral bioavailability. The proportion of the drug, when taken orally, which is available to the user is both poor and erratic. Melatonin's absolute oral bioavailability has been shown to be approximately from approximately 15% in some studies to as low as 2.5% in others and peak plasma concentrations can vary over 20 fold range. DeMuro R L, Nafziger A N, Blask D E, Menhinick A M, Bertino J S: Journal of Clinical Pharmacology 2000: 40; 781; Di W L, Kadva A, Johnston A, Silman R: New England Journal of Medcine 1997: 336; vol. 14, 1028. Thus, oral administration of melatonin in currently available preparations does not provide for rapid onset of action, and its poor and erratic GI absorption make it an unsuitable route of administration.
Several sublingual, buccal, orally dissolving tablets and films containing melatonin are also available commercially. For example, transmucosal formulations are described in WO 1996/030013 and U.S. Pat. No. 5,688,520. However, in these formulations, melatonin is compounded in its undissolved, or solid, state. For any drug to be absorbed into the bloodstream, it must be dissolved, i.e., in solution. Due to melatonin's poor water solubility much of the dosage from any currently available preparation is swallowed undissolved in the saliva, leading to poor and erratic absorption in the GI tract. Accordingly, hormone drugs such as melatonin having low to poor water solubility, are expected to be poorly suited for buccal or sublingual administration.
Other routes of administration for melatonin, including nasal and oral sprays have been considered. U.S. Pat. No. 6,007,834. However, sprays are less desirable because of inherent compliance issues such as improper manipulation of the actuator, swallowing of the dosage before dissolution of the drug, and the restrictions on usage when the patient has sinus congestion or a head cold. Again poor solubilization of the dosage will lead to poor absorption. This again leads to erratic and poor melatonin bioavailability. Therefore sprays are not the optimal route for routine melatonin administration.
Moving on to Valerian, valerian root extract has long been used as a herbal remedy for the treatment of sleep disorders. It has been postulated that the mechanism of action related to valerian extract is related to the soporific action of the valeprotiates and the GABA minergic action of valerenic acid. Thus the increased absorption of these essential compounds and their increased bioavailability through the complexation in the present invention allows for both faster absorption at the buccal mucosa and enhanced absorption at the small intestinal layer providing both rapid and prolonged effect within the same dosage form.
Research into the use of Valerian root extracts to treat symptoms of insomnia has shown extremely high variability of absorption both inter individual and intra individual and has therefore not met commercial success to date. That this high variability of effect and absorption is probably due to high variability of metabolism by the liver.
Accordingly, there is a need in the arts to provide rapid and consistent delivery of a sleep inducing hormone having low to poor water solubility, such as melatonin and valerian extract.